Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, following Single- and Multiple-Ascending Doses in Healthy Adults.

Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.

BACKGROUND: Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking. METHODS: We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed. RESULTS: In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation. CONCLUSIONS: Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).

Pharmacokinetic/pharmacodynamic and safety study of a single dose of evolocumab 140 mg in healthy Chinese subjects.

OBJECTIVE: Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. MATERIALS AND METHODS: This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. RESULTS: 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) µg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×µg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×µg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. CONCLUSION: A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.

Romosozumab in Skeletally Mature Adults with a Fresh Unilateral Tibial Diaphyseal Fracture: A Randomized Phase-2 Study.

BACKGROUND: Romosozumab is an antibody that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. A double-blinded, randomized, phase-2, dose-finding trial was performed to evaluate the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures. METHODS: Patients (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups. Patients received subcutaneous injections of romosozumab or the placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary outcome was the time to radiographic evidence of healing ("radiographic healing") analyzed after the week-24 assessments had been completed for all patients. RESULTS: A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group. The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95% confidence interval [CI]: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference. There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function. The safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not accelerate tibial fracture-healing in this patient population. Additional studies of patients at higher risk for delayed healing are needed to explore the potential of romosozumab to accelerate tibial fracture-healing. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A Randomized, Placebo-Controlled Study of Romosozumab for the Treatment of Hip Fractures.

BACKGROUND: Romosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures. METHODS: Patients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed "Up & Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH). RESULTS: A total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo. CONCLUSIONS: Romosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

A Phase 1, Randomized, Double-Blind, Single-Dose, Placebo-Controlled Safety, Tolerability, And Pharmacokinetic/Pharmacodynamic Study Of Evolocumab In Healthy Chinese Subjects.

PURPOSE: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects. SUBJECTS AND METHODS: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast). RESULTS: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 µg/mL and 67.6 (15.2) µg/mL, respectively, and mean (SD) AUClast was 166 (55) day·µg/mL and 1110 (274) day·µg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo). CONCLUSION: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.

Influence of Renal Function on Evolocumab Exposure, Pharmacodynamics, and Safety.

We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open-label, parallel-design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end-stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140-mg dose of evolocumab. The effects of evolocumab treatment on low-density lipoprotein cholesterol (LDL-C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere-Terpstra trend test; Cmax , P = .23; AUClast , P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by Cmax and AUClast , in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL-C-lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.

Pharmacokinetics, Biotransformation, and Excretion of [14C]Etelcalcetide (AMG 416) Following a Single Microtracer Intravenous Dose in Patients with Chronic Kidney Disease on Hemodialysis.

Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven D-aminoacids with an L-cysteine linked to a D-cysteine by a disulfide bond. A single intravenous dose of [14C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [14C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide D-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and L-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected.

Performance of the pegfilgrastim on-body injector as studied with placebo buffer in healthy volunteers.

OBJECTIVE: The pegfilgrastim on-body injector (OBI) is a single-use, disposable, battery-powered injector that is designed to automatically deliver a single subcutaneous dose of pegfilgrastim beginning approximately 27 hours after activation and continuing over approximately 45 minutes. In this open-label study, we assessed performance of the OBI delivering placebo buffer in healthy volunteers. RESEARCH DESIGN AND METHODS: Healthy men and women aged 18-55 years, with a body mass index of 18-35 kg/m2, were enrolled. OBIs were activated by filling them with placebo buffer, and two injectors were applied concurrently to each subject: one to the abdomen and one to the back of the upper arm. Subjects were monitored for substantial leakage during and after administration. MAIN OUTCOME MEASURES: The primary endpoint of the study was successful delivery of placebo buffer based on a composite of the following: no substantial leakage during or after administration, green status light indicator on the injector during and after administration, and fill indicator bar at the empty position after administration. The secondary endpoint was the incidence of treatment-emergent adverse events (AEs). RESULTS: Of the 150 subjects enrolled, 149 (99.3%) completed the study. Study subjects were 48.0% men, and 52.0% women; 47.3% were white, 35.3% black or African American, 12.7% Asian, and 4.7% other. Mean (SD) age was 35.9 (10.8) years. Of the 297 total deliveries, 292 (98.3%) were considered successful: 147/149 (98.7%; 95% confidence interval [CI]: 95.2%-99.6%) to the abdomen and 145/148 (98.0%; 95% CI: 94.2%-99.3%) to the back of the upper arm. Five deliveries were considered unsuccessful: two due to hazard alarms, and three due to substantial leakage. The most common treatment-emergent AEs (in >2% of subjects overall) by preferred term were medical device site reaction (20.7%), catheter-site hemorrhage (8.7%), and headache (3.3%). No serious AEs were reported. CONCLUSIONS: The pegfilgrastim OBI was well tolerated, and deliveries of placebo buffer were successful 98.3% of the time. The generalizability of these results may be limited by the conduct of this study in healthy subjects in a controlled environment.

Evaluation of Evolocumab (AMG 145), a Fully Human Anti-PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment.

Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open-label, parallel-group study evaluated the pharmacokinetics of evolocumab in hepatic-impaired (Child-Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140-mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL-C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere-Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration -34%; mean area under the concentration-time curve (AUC) -47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL-C reductions in the healthy, mild, and moderate groups were -57% (-64% to -48%), -70% (-75% to -63%), and -53% (-61% to -43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment.

An open-label study in healthy men to evaluate the risk of seminal fluid transmission of denosumab to pregnant partners.

AIMS: Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner. METHODS: An open-label, single-dose study in 12 healthy men was conducted over a 106-day period. Subjects received a single subcutaneous dose of 60-mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded. RESULTS: Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax ) was 6170 (2070) ng ml(-1) (serum) and 100 (81.9) ng ml(-1) (seminal fluid). The median time to Cmax (tmax ) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast ) was 333 000 (122 000) day•ng ml(-1) (serum) and 5220 (4880) day•ng ml(-1) (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived 'no effect level' for denosumab. CONCLUSIONS: These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.

A clinical therapeutic protein drug-drug interaction study: coadministration of denosumab and midazolam in postmenopausal women with osteoporosis.

Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator.

Readiness of wait-listed black patients to pursue live donor kidney transplant.

CONTEXT: For adults with end-stage kidney disease, live donor kidney transplant (LDKT) has better outcomes than long-term dialysis and deceased donor kidney transplant. However, black patients receive LDKT at a much lower rate than adults of any other race or ethnicity. OBJECTIVE: To examine the LDKT readiness stage of black patients on the transplant waiting list and its association with LDKT knowledge, concerns, and willingness. DESIGN: Cross-sectional analysis of baseline data from a randomized controlled trial to improve knowledge and reduce concerns about LDKT.Patients and Setting-One hundred fifty-two black patients on the kidney transplant waiting list at a single transplant center in the northeastern United States. MAIN OUTCOME MEASURES: LDKT readiness stage, knowledge, concerns, and willingness to talk to others about living donation. RESULTS: Sixty percent of patients were not considering or not yet ready to pursue LDKT, and only 11% had taken action to talk to family members or friends about the possibility of living kidney donation. Patients in later stages of LDKT readiness (ie, who had talked to others about donation or were preparing to do so) had significantly more knowledge (P<.001), fewer concerns (P=.002), and more willingness (P=.001) to talk to others about living donation than those in earlier readiness stages. CONCLUSIONS: The large percentage of black patients who are in the earlier stages of LDKT readiness may account for the low rate of LDKT in this patient population at our transplant center. Innovative and tailored LDKT educational strategies for black patients are needed to help reduce racial disparities in LDKT.

Making house calls increases living donor inquiries and evaluations for blacks on the kidney transplant waiting list.

BACKGROUND: Blacks receive live donor kidney transplant (LDKT) less often than patients of all other races. We evaluated the effectiveness of educational interventions in removing barriers to LDKT for blacks. METHODS: Patients were randomized to three interventions in which health educator(s) delivered an intervention to (a) the patient and his/her guests in the patient's home (house calls [HC], n=54), (b) clusters of patients and their guests in the transplant center (group based [GB], n=49), and (c) the individual patient alone in the transplant center (individual counseling [IC], n=49). RESULTS: At the 2-year endpoint, 15% (n=8), 8% (n=4), and 6% (n=3) of HC, GB, and IC patients, respectively, received LDKT (P=0.30). Patients in the HC group were more likely than patients in the GB and IC groups to have at least one donor inquiry (82% vs. 61% vs. 47%, P=0.001) and evaluation (65% vs. 39% vs. 27%, P<0.001). Patients in the HC group also were more likely to have higher knowledge, fewer concerns, and higher willingness to talk to others about donation 6 weeks after intervention. CONCLUSIONS: These findings underscore the importance of including the patient's social network in LDKT education and the potential of the HC intervention to reduce racial disparity in LDKT rates.

RANKL inhibition with denosumab does not influence 3-year progression of aortic calcification or incidence of adverse cardiovascular events in postmenopausal women with osteoporosis and high cardiovascular risk.

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with bone mineral density (BMD). The osteoprotegerin (OPG)/receptor activator of NF-κB (RANK)/RANK ligand (RANKL) system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2363 postmenopausal women with osteoporosis (1142 placebo, 1221 DMAb), selected from 7808 participants in the FREEDOM trial (3906 placebo, 3902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semiquantitative method from lateral spine X-rays. Change in AC score from baseline to 12 (n = 1377), 24 (n = 1231), and 36 months (n = 1045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score >0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60-90), 88% were white, and 77% had AC score >0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.

Willingness to pursue live-donor kidney transplantation among waitlisted patients infected with human immunodeficiency virus (HIV): a preliminary investigation.

We show that HIV-infected waitlisted patients (n=33) had significantly lower knowledge (P<0.001), more concerns (P=0.01), and lower willingness to pursue live-donor kidney transplantation (LDKT; P=0.02) than matched noninfected patients. The majority (78%) of patients felt that their HIV status reduced their chance of LDKT. Although limited to a single center and a small sample, our data suggest that HIV-infected patients who are waitlisted for kidney transplantation may need more education about the potential benefits of LDKT and may benefit from patient-centered decision support to facilitate a risk-benefit assessment consistent with their preferences and values.

CaSR-mediated interactions between calcium and magnesium homeostasis in mice.

Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading.

The "House Calls" trial: a randomized controlled trial to reduce racial disparities in live donor kidney transplantation: rationale and design.

Despite a substantially lower rate of live donor kidney transplantation among Black Americans compared to White Americans, there are few systematic efforts to reduce this racial disparity. This paper describes the rationale and design of a randomized controlled trial evaluating the comparative effectiveness of three different educational interventions for increasing live donor kidney transplantation in Black Americans. This trial is a single-site, urn-randomized controlled trial with a planned enrollment of 180 Black Americans awaiting kidney transplantation. Patients are randomized to receive transplant education in one of three education conditions: through group education at their homes (e.g., House Calls), or through group (Group-Based) or individual education (Individual Counseling) in the transplant center. The primary outcome of the trial is the occurrence of a live donor kidney transplant, with secondary outcomes including living donor inquiries and evaluations as well as changes in patient live donor kidney transplantation readiness, willingness, knowledge, and concerns. Sex, age, dialysis status, and quality of life are evaluated as moderating factors. Findings from this clinical trial have the potential to inform strategies for reducing racial disparities in live donor kidney transplantation. Similar trials have been developed recently to broaden the evaluation of House Calls as an innovative disparity-reducing intervention in kidney transplantation.

Effects of denosumab on fracture and bone mineral density by level of kidney function.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.